Spinal P2X₃ receptors blockade reverses paclitaxel-induced allodynia in rats

Allodynia to mechanical stimuli is one of the most prevalent symptoms in paclitaxel-treated cancer patients. Paclitaxel induces ATP release from nerve terminals; thus, peripheral primary sensory neurons can be sensitized by ATP, as a large subgroup expresses purinergic P2X_2/3 and P2X₃ receptors. In this study, we examined the role of P2X_2/3 and P2X₃ receptors in paclitaxel-treated rats with allodynia. We assessed the paw withdrawal threshold as an allodynia test on paclitaxel-treated rats and evaluated the intrathecal and systemic effects of purinergic receptor antagonists and the transient knockdown of P2X₃ receptor expression in male and female allodynic rats. A single dose of paclitaxel decreased the paw withdrawal threshold to mechanical stimulation in both sexes. Pharmacological blockade of spinal P2X₃ and P2X_2/3 receptors with Ro-51, TNP-ATP, and systemic suramin reversed allodynia in paclitaxel-treated rats. In addition, the transient knockdown of P2X₃ receptors with intrathecal siRNA administration had an antiallodynic effect that lasted until 72 h post-transfection. Paclitaxel produced an increase in the P2X₃ receptor expression in dorsal root ganglia but not in dorsal horn spinal cord. In conclusion, spinal P2X_2/3 and P2X₃ receptors have a significant role in allodynia to mechanical stimulation in paclitaxel-treated rats, regardless of sex. Therefore, the blockade of these receptors could be an alternative pharmacological target for alleviating sensory symptoms of paclitaxel-induced peripheral neuropathy in patients with cancer.